Ropinirole

Dosage and Administration (2.2, 2.3) 8/2014 Contraindications (4) 8/2014 Warnings and Precautions (5.5, 5.7) 8/2014

1 INDICATIONS AND USAGE Ropinirole extended-release tablets are non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (1.1) 1.1 Parkinson's Disease Ropinirole extended-release tablets are indicated for the treatment of Parkinson’s disease.

2 DOSAGE AND ADMINISTRATION Ropinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and not be chewed, crushed, or divided. ( 2.1 ) The recommended starting dose is 2 mg taken once daily for 1 to 2 weeks; the dose should be increased by 2 mg/day at 1 week or longer intervals. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. ( 2.2 , 14.2 ) Renal Impairment: In patients with end-stage renal disease on hemodialysis, the maximum recommended dose is 18 mg/day. ( 2.2 ) If ropinirole extended-release tablets must be discontinued, it should be tapered gradually over a 7-day period; retitration of ropinirole extended-release tablets may be warranted if therapy is interrupted. ( 2.1 , 2.2 ) Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets; the initial switching dose of ropinirole extended-release tablets should approximately match the total daily dose of immediate-release ropinirole. ( 2.3 ) 2.1 General Dosing Recommendations Ropinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology (12.3) ]. Tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions. In fixed-dose studies designed to characterize the dose response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day [see Clinical Studies ( 14.1 and 14.2 )] . Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower. Ropinirole extended-release tablets should be discontinued gradually over a 7-day period [see Warnings and Precautions ( 5.9 )] . Renal Impairment No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied. 2.3 Switching from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets Patients may be switched directly from immediate-release ropinirole tablets to ropinirole extended-release tablets. The initial dose of ropinirole extended-release tablets should approximately match the total daily dose of the immediate-release formulation of ropinirole, as shown in Table 1. Table 1. Conversion from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets Immediate-Release Ropinirole Tablets Ropinirole Extended-Release Tablets Total Daily Dose (mg) Total Daily Dose (mg) 0.75 to 2.25 2 3 to 4.5 4 6 6 7.5 to 9 8 12 12 15 16 18 18 21 20 24 24 Followin …

3 DOSAGE FORMS AND STRENGTHS • 2 mg, pink, oval-shaped, unscored, film-coated tablets, debossed with and 658 on one side and plain on the other side. • 4 mg, blue, oval-shaped, unscored, film-coated tablets, debossed with and 659 on one side and plain on the other side. • 6 mg, white to off-white, oval-shaped, unscored, film-coated tablets, debossed with and 640 on one side and plain on the other side. • 8 mg, red, oval-shaped, unscored, film-coated tablets, debossed with and 660 on one side and plain on the other side. • 12 mg, yellow, oval-shaped, unscored, film-coated tablets, debossed with and 661 on one side and plain on the other side. Tablets: 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg ( 3 ) 54887e95-figure-01 54887e95-figure-02 54887e95-figure-03 54887e95-figure-04 54887e95-figure-05

4 CONTRAINDICATIONS Ropinirole extended-release tablets are contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or any of the excipients. History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the label: Hypersensitivity [see Contraindications ( 4 ) ] Falling asleep during activities of daily living and somnolence [see Warnings and Precautions ( 5.1 ) ] Syncope [see Warnings and Precautions ( 5.2 )] Hypotension/orthostatic hypotension [see Warnings and Precautions ( 5.3 )] Elevation of blood pressure and changes in heart rate [see Warnings and Precautions ( 5.4 ) ] Hallucinations/psychotic-like behavior [see Warnings and Precautions ( 5.5 ) ] Dyskinesia [see Warnings and Precautions ( 5.6 ) ] Impulse control/compulsive behaviors [see Warnings and Precautions ( 5.7 ) ] Withdrawal-emergent hyperpyrexia and confusion [see Warnings and Precautions ( 5.8 ) ] Withdrawal symptoms [see Warnings and Precautions ( 5.9 ) ] Fibrotic complications [see Warnings and Precautions ( 5.10 ) ] Retinal pathology [see Warnings and Precautions ( 5.11 ) ] Most common adverse reactions (incidence for ropinirole extended-release all doses at least 5% greater than placebo in either a flexible- or fixed-dose study) in patients with advanced Parkinson’s disease were nausea, dyskinesia, dizziness, and hallucination. (6.1 ) Most common adverse reactions (incidence for ropinirole extended-release all doses at least 5% greater than placebo in fixed-dose study) in patients with early Parkinson’s disease not taking L-dopa were nausea, somnolence, sudden onset of sleep, hypertension, and headache. In a flexible-dose study in patients with early Parkinson's, the most common adverse reactions (at least 5% incidence for ropinirole extended-release) were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice. During the premarketing development of ropinirole extended-release, patients with advanced Parkinson’s disease received ropinirole extended-release or placebo as adjunctive therapy with L-dopa in a flexible-dose clinical trial. In a flexible-dose trial, patients with early Parkinson's disease were treated with ropinirole extended-release or the immediate-release formulation of ropinirole without L-dopa. In addition, placebo-controlled, fixed-dose, postmarketing trials evaluated the dose response of ropinirole extended-release in patients with advanced Parkinson’s disease taking L-dopa and in patients with early Parkinson’s disease without concomitant L-dopa. Advanced Parkinson’s Disease (with L-dopa) Study 1 was a 24-week, double-blind, placebo-controlled, flexible-dose trial in patients with advanced Parkinson's disease. In Study 1, the most commonly observed adverse reactions in patients treated with ropinirole extended-release (incidence at least 5% greater than placebo) were dyskinesia, nausea, dizziness, and hallucinations. In Study 1, approximately 6% of patients treated with ropinirole extended-release discontinued treatment due to adverse reactions compared with 5% of patients who received placebo. The most common adverse reaction in patients treated with ropinirole extended-release causing discontinuation of treatment with ropinirole extended-release in Study 1 was hallucination (2%). Table 2 lists adverse reactions that occurred in at least 2% (and were numerically greater than placebo) of patients with advanced Parkinson’s disease treated with ropinirole extended-release who participated in Study 1. In this trial, either ropinirole extended-release or placebo was used as an adjunct to L-dop …

7 DRUG INTERACTIONS Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole extended-release tablets may be required. ( 7.1 , 12.3 ) Hormone replacement therapy (HRT): Starting or stopping HRT treatment may require dose adjustment of ropinirole extended-release tablets. ( 7.2 , 12.3 ) Dopamine antagonists (e.g., neuroleptics metoclopramide): May reduce efficacy of ropinirole extended-release tablets. ( 7.3 ) 7.1 Cytochrome P450 1A2 Inhibitors and Inducers In vitro metabolism studies showed that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole extended-release tablets, adjustment of the dose of ropinirole extended-release tablets may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, with immediate-release ropinirole increases the AUC and C max of ropinirole [see Clinical Pharmacology ( 12.3 ) ]. Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology ( 12.3 ) ]. 7.2 Estrogens Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy) reduced the clearance of ropinirole. Starting or stopping hormone replacement therapy may require adjustment of dosage of ropinirole extended-release tablets [see Clinical Pharmacology ( 12.3 ) ]. 7.3 Dopamine Antagonists Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of ropinirole extended-release tablets.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ropinirole extended-release tablets in pregnant women. In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the MRHD for Parkinson’s disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination [see Data] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated populations is unknown. Data Animal Data: Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the 2 highest doses. These doses were also associated with maternal toxicity. The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinson’s disease (24 mg/day) on a body surface area (mg/m 2 ) basis. No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on a mg/m 2 basis). In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone. This drug combination was also associated with maternal toxicity. Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose. The no-effect dose of 1 mg/kg/day is less than the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary There are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ropinirole extended-release tablets and any potential adverse effects on the breastfed infant from ropinirole or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole extended-release tablets is to be individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [see Clinical Pharmacology (12.3) ]. In flexible-dose clinical trials of ropinirole extended-release tablets, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving ropinirole extended-release tablets, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). In these trials, the incidence …

12.1 Mechanism of Action Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D 2 -type receptors within the caudate-putamen in the brain.

11 DESCRIPTION Ropinirole Extended-Release Tablets, USP contain ropinirole, a non-ergoline dopamine agonist as the hydrochloride salt. The chemical name of ropinirole hydrochloride, USP is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one and has a molecular formula of C 16 H 24 N 2 O•HCl. The molecular weight is 296.84 (260.38 as the free base). The structural formula is: Ropinirole hydrochloride, USP is a white to yellow solid with a melting range of 243o to 250oC and a solubility of 133 mg/mL in water. Each Ropinirole Extended-Release Tablet, USP for oral administration is oval-shaped and contains 2.28 mg, 4.56 mg, 6.84 mg, 9.12 mg, or 13.68 mg of ropinirole hydrochloride, USP equivalent to ropinirole 2 mg, 4 mg, 6 mg, 8 mg, or 12 mg, respectively. Inactive ingredients consist of colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, and titanium dioxide. In addition the 2 mg tablet also contains iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl-alcohol, and talc. The 4 mg tablet also contains black iron oxide, FD&C Blue #2/Indigo Carmine Aluminum Lake, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake, polydextrose, polyethylene glycol, and triacetin. The 6 mg tablet also contains polyethylene glycol, polyvinyl-alcohol, and talc. The 8 mg tablet also contains iron oxide red, polyethylene glycol, polyvinyl-alcohol, and talc. The 12 mg tablet also contains iron oxide yellow, polyethylene glycol, polyvinyl-alcohol, and talc. This drug product conforms to USP Dissolution Test 3. 54887e95-figure-06

10 OVERDOSAGE The symptoms of overdose with ropinirole are generally related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. In the Parkinson’s disease program, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole. The largest overdose reported with immediate-release ropinirole in clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.

16 HOW SUPPLIED/STORAGE AND HANDLING Each capsule shaped, film coated tablet contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows: 2 mg: pink tablets debossed with ‘L191’ NDC 62332-107-30 bottle of 30 tablets with child-resistant closure NDC 62332-107-90 bottle of 90 tablets with child-resistant closure NDC 62332-107-31 bottle of 100 tablets with child-resistant closure NDC 62332-107-71 bottle of 500 tablets NDC 62332-107-91 bottle of 1000 tablets NDC 62332-107-10 carton of 100 (10X10) unit dose tablets 4 mg: light brown tablets debossed with ‘L193’ NDC 62332-108-30 bottle of 30 tablets with child-resistant closure NDC 62332-108-90 bottle of 90 tablets with child-resistant closure NDC 62332-108-31 bottle of 100 tablets with child-resistant closure NDC 62332-108-71 bottle of 500 tablets NDC 62332-108-91 bottle of 1000 tablets NDC 62332-108-10 carton of 100 (10X10) unit dose tablets 6 mg: white to off white tablets debossed with ‘L321’ NDC 62332-109-30 bottle of 30 tablets with child-resistant closure NDC 62332-109-90 bottle of 90 tablets with child-resistant closure NDC 62332-109-31 bottle of 100 tablets with child-resistant closure NDC 62332-109-71 bottle of 500 tablets NDC 62332-109-91 bottle of 1000 tablets NDC 62332-109-10 carton of 100 (10X10) unit dose tablets 8 mg: dark brown to red tablets debossed with ‘L194’ NDC 62332-110-30 bottle of 30 tablets with child-resistant closure NDC 62332-110-90 bottle of 90 tablets with child-resistant closure NDC 62332-110-31 bottle of 100 tablets with child-resistant closure NDC 62332-110-71 bottle of 500 tablets NDC 62332-110-91 bottle of 1000 tablets NDC 62332-110-10 carton of 100 (10X10) unit dose tablets 12 mg: light green tablets debossed with ‘L195’ NDC 62332-111-30 bottle of 30 tablets with child-resistant closure NDC 62332-111-90 bottle of 90 tablets with child-resistant closure NDC 62332-111-31 bottle of 100 tablets with child-resistant closure NDC 62332-111-71 bottle of 500 tablets NDC 62332-111-91 bottle of 1000 tablets NDC 62332-111-10 carton of 100 (10X10) unit dose tablets Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP.